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Can an Anti-Ageing Gene Rewind a Heart's Age?

An anti-ageing gene discovered in a population of centenarians has been shown to rewind the heart's biological age by 10 years.

The aging heart naturally incurs a "progressive decline in function and perfusion" that available treatments "cannot halt", explained the authors of a new study, published in Cardiovascular Research. However, due to favourable gene-environment interaction, carriers of healthy mutant genes often live to 100 years or more and remain in good health, they pointed out.

Associated with exceptional longevity, carriers of healthy mutant genes - like those living in ‘blue zone’ regions in the world where it is speculated that people live longer than average - are also less prone to cardiovascular complications. Scientists believe the gene helps to keep their hearts young by protecting them against diseases linked to ageing, such as heart failure.

Paolo Madeddu, professor of experimental cardiovascular medicine, Bristol Heart Institute, University of Bristol, and one of the study’s authors, explained: "The heart and blood vessel function is put at stake as we age. However, the rate at which these harmful changes occur is different among people. Smoking, alcohol, and sedentary life make the ageing clock faster. Whereas eating well and exercising delay the heart’s ageing clock. In addition, having good genes inherited from parents can help to stay young and healthy."

Rewind the Heart’s Biological Clock

The scientists, from the University of Bristol and the MultiMedica Group in Italy, highlighted that carriers of a longevity-associated variant (LAV) of the BPIFB4 gene "enjoy prolonged health spans and lesser cardiovascular complications", and that supplementation of LAV-BPIFB4 via an adeno-associated viral vector "improves cardiovascular performance" in limb ischaemia, atherosclerosis, and diabetes models.

Annibale Puca, head of the laboratory at the IRCCS MultiMedica and professor at the University of Salerno, highlighted that "gene therapy with the healthy gene in mouse models of disease has already been shown to prevent the onset of atherosclerosis, vascular ageing, and diabetic complications, and to rejuvenate the immune system".

For the study, the researchers set out to investigate if the LAV-BPIFB4 gene could address the "unmet therapeutic need" to delay the heart’s spontaneous aging.

They performed immunohistological studies on hearts explanted from elderly patients with ischaemic heart failure, and healthy controls. The researchers found a "remarkable reduction" in vessel coverage by pericytes in failing hearts. "This defect was attenuated in patients carrying the homozygous LAV-BPIFB4 genotype," they said.

Cardiac Rejuvenation and Protection

The researchers found that a single administration of the mutant anti-ageing gene, which had been previously proved particularly frequent in centenarians, "halted the decay" of heart function in middle-aged mice. Even more remarkably, when given to elderly mice, whose hearts exhibit the same alterations observed in elderly patients, the gene "rewound" the heart’s biological clock age by the human equivalent of "more than 10 years", they said.

Monica Cattaneo, a researcher of the MultiMedica Group in Milan, Italy, and first author of the study, said: "The cells of the elderly patients, in particular those that support the construction of new blood vessels, called 'pericytes', were found to be less performing and more aged." She explained that by adding the "longevity gene/protein", they witnessed a process of cardiac "rejuvenation".

"The cardiac cells of elderly heart failure patients had resumed functioning properly, proving to be more efficient in building new blood vessels," she enthused.

The breakthrough offers a potential target for patients with heart failure, suggested the authors.

"Centenarians pass their healthy genes to their offspring. The study demonstrates for the first time that a healthy gene found in centenarians could be transferred to unrelated people to protect their hearts," said the authors.

Professor Madeddu added: "Our findings confirm the healthy mutant gene can reverse the decline of heart performance in older people." He said the team were now exploring if giving the protein instead of the gene can also work, since "a treatment based on a protein is safer and more viable than gene therapy," he indicated.

"Other mutations might be found in the future with similar or even superior curative potential than the one investigated by this research," proposed the authors, who believe their findings may fuel a "new wave of treatments" inspired by the genetics of centenarians. 

Prof Puca effused: "We have a new confirmation and enlargement of the therapeutic potential of the gene/protein. We hope to test its effectiveness soon in clinical trials on patients with heart failure."

Professor James Leiper, associate medical director at the British Heart Foundation, said: "We all want to know the secrets of ageing and how we might slow down age-related disease. Our heart function declines with age but this research has extraordinarily revealed that a variant of a gene that is commonly found in long-lived people can halt and even reverse ageing of the heart in mice.

"This is still early-stage research," he cautioned, but hoped it could one day provide a "revolutionary" way to treat people with heart failure, and "even stop the debilitating condition from developing in the first place", he said.

The study was funded by the British Heart Foundation and the Italian Ministry of Health. All the other authors declare no conflicts of interest.